3-(Alpha-trifluoromethylarylacetamido)-1,4-cyclo(1,-carboxyl)alkylenethio)-azetidin-2-one derivatives

ABSTRACT

3-( Alpha -Trifluoromethylarylacetamido)-1,4-(cyclo-(1&#39;&#39;carboxy)alkylenethio)azetidin-2-one derivatives possessing antibacterial activity are produced by the reaction of 3,3,3trifluoro-2-phenylpropanoic acid or 3,3,3-trifluoro-2-phydroxyphenylpropanoic acid and a 3-amino-1,4-(cyclo(1&#39;&#39;carboxy)alkylenethio)-azetidin-2-one derivative in the presence of a condensing agent or by conversion of the propanoic acid derivative to an acid halide.

United States Patent 1 Teller et al.

[ S-(ALPHA- TRIFLUOROMETHYLARYLACETAMIDO l,4-CYCLO(l,-CARBOXYL)ALKYLENETHI- O)-AZETlDlN-2-ONE DERIVATIVES [75] lnventors:Daniel M, Teller, Devon; John H.

Sellstedt; Charles J. Gainosso, both of King of Prussia. all of Pa.

[73} Assignee: American Home Products Corporation, New York. NY.

[22] Filed: May 16, 1973 [21] Appl. No: 360,857

[52] U.S. Cl 260/243 C; 424/246; 260/239];

424/271 [5 l] Int. Cl. C07d 99/24; C07d 99/16 [58] Field of Search260/243 C [451 Apr. 22, 1975 [56] References Cited UNITED STATES PATENTS3.64l.02l 2/l972 Ryan 260/243 C Primary E.\'mninerNich0las S. RizzoAlmrney, Agent. or FirmRichard K. Jackson [57] AISTRACT 3-(a-Trifluoromethylarylacetamido )-l ,4-[cyclo-( lcarboxy)alkylenethioIazetidin-Z-one derivatives possessing antibacterialactivity are produced by the reaction of3.3,3-trifluoro-Z-phenylpropanoic acid or 3.3.-3-trifluoro-2-p-hydroxyphenylpropanoic acid and a 3- amino- 1 ,4-[cyclo(l '-carboxy)alkylenethio1-azetidin- 2-one derivative in the presence ofa condensing agent or by conversion of the propanoic acid derivative toan acid halide.

3 Claims, No Drawings S-(ALPHA- TRIFLUOROMETHYLARYLACETAMIDO)-l,4-CYCLO(1,-CARBOXYL)ALKYLENETHIO)- AZETIDIN-Z-ONE DERIVATIVES BACKGROUNDOF THE INVENTION Acylated 7aminocephalosporanic acid derivativescontaining a chloroalkyl group in Z-position of the moiety are disclosedby Kujoshi Hattori in Japanese Pat. No. 29,258/69 (Derwent Report No.41452).

DESCRIPTION OF THE INVENTION In accordance with this invention there isprovided a group of azetidin-2-one derivatives which are activeantibacterials. More specifically. the compounds ofthis invention may begenerically termed 3-[a-trifluoromethylphenyl andp-hydroxyphenyl)acetamido1-l.4- [cyclo( l-carboxyl)alkylenethioll-azetidin-Z-one derivatives which present thestructural formula:

COR

wherein R is a member selected from the group consisting of H and OI-I.

R is a member selected from the group consisting of -H and an alkalimetal cation. and

Y is a member selected from the group consisting of CH (311 a C and CHC= CH in which R;, is --H. (lower)alkanoyloxy.

N-'-N II II N-pyridim'nm, SC C--CH and N N a: ll

The expression l.4-[cyclo( l '-carboxy )alkylenethio. used in thegeneric name for the compounds of this invention. is intended to embracethe I-CZlI'bOX) bridge member equation F3CCHC02H H NR condensing}F.3CCHCONHR1 agent in which R is H or Oh and the condensing agent issuch as carbonyldiimidazole. dicyclohexylcarbodiimide.dicyclohexylcarbodiimide in the presence of N-hydroxysuccinimide or 1-hydroxybenzotriazole. isobutylchloroformate, and the like. These andsimilar condensing agents which are operable in the preparation of theantibacterial agents of this invention are presented in Spencer et. al..J. Med. Chem. 15. pp 333-335 (1972); Klausner et.al.. Synthesis. pp453-463 (197.2) and US. Pat. No. 3.338.896.

Alternatively, the a-trifluoromethylarylacetic acid precursor may beconverted by known methods to an acid halide which is then used inaqueous medium to acylate the free amino group of either a tertiaryamine salt or an alkali metal salt of the 3-amino azetidinonederivative. In addition. the oz-trifluoromethylarylacetic acid halideprecursor may be used to react in organic.

solution with either a tertiary amine salt or a silylated.phosphorylated or saccharinated derivative of the 3- aminoazetidinonereactant. In each case. the protecting groups are readily removed byhydrolysis at the conclusion of the reaction.

The 3.3.3-trifluoro-2-phenyl (and phydroxyphenyl)propanoic acidreactants are prepared by the technique of Aaron et.al., J. Org. Chem.32, pp. 27972803 (1967).

The compounds of this invention are antibacterial agents effectiveagainst gram-positive and gramnegative test organisms as well aspenicillin resistant staphylococcus at an inhibitory concentration at orbelow 250 micrograms per milliliter using the well known andscientifically accepted agar serial dilution technique. Thus. thecompounds of this invention are useful in the fields of comparativepharmacology and microbiology and may be used as growth promoters inanimals and for the treatment of infections amenable to treatment withpenicillins and cephalosporins.

The following examples are presented for purposes of illustrating theinvention and are not to be construed as limitations upon the true scopeof the contribution. The biological activity data presented at theconclusion of each example illustrate the compounds activity againstspecific bacteria of the designated strain in terms of the minimuminhibitory concentration of the compound in micrograms per milliliter tocompletely inhibit the test organism. The abbreviations for eachbacteria are ST AL' Staphylococcus aureus BA SL Bacillus suhtilis NE CANeisseria catarrhalis HE SP Hcrellea species ES CO Escherichia coli PR\L' Proteus vulgaris SA PA Salmonella paratyphi BO BR Bordetellahrochiseptica EN AE Enterohacter aerogenes ES lN Escherichia intermediaKl. PN Klehsiella pneumoniae In the working examples. the expression ACArefers to aminocephalosporanic acid. ADCA refers toaminodesacetoxy-cephalosporanic acid. acid. and APA refers toaminopenicillanic acid.

EXAMPLE 1 7-(3.3.3-Trifluoro-Z-phenylpropionamido)cephalosporanic acid.

To a solution of 3.3.3-trifluoro-2-phenylpropanoic acid (0.5] g, 0.0025moles) in dry dimethylformamide (3.0 ml) at room temperature is addedcarbonyl diimidazole (0.41 g. 0.0025 moles) under nitrogen. Carbondioxide evolution begins immediately. After 30 minutes at roomtemperature. the residual carbon dioxide is removed under vacuum. Themixture is cooled to lC. and a solution of 7-ACA (0.68 g. 0.00095 moles)in dry methylene chloride (l0 ml.) containing triethyl amine l .04 ml.)is added all at once. After stirring 2 hours at room temperature. themixture was concentrated at below 40C. n-Butanol (2.5 ml.) is added.then potassium ethyl hexanoate (1.25 ml. of 2M solution in n-butanol).After stirring minutes. diethyl ether 100 ml.) is added. the productfiltered and dried in vacuo at room temperature to yield a tan solid,mp. l50200C. (decomp.); x,,,,,,'"" 5.52. 5.73. 6.20 a; NMR has 187 and2.02 ppm methyl peaks.

3-Methyl-8-oxo-7-( 3,3 .3-trifluoro-2- 2.55 ppm peaks.

BA so 6633 7.81

ST AU 6538P 15.6

ST AU SMITH 15.6

ST AU 53-l80 62.5

ST AU CHP 125 x1. PN 10031 250 EXAMPLE 3 6-( 3.3.3-Trifluoro-2-phenylpropionamido )penicillanic acid.

Using the procedure described in Example 1 but substituting .6-APA (0.54g, 0.0025 moles) for 7-ACA gives the title compound. mp. l45160C.(decomp.); A,,,,,,' 5.54. 6.20 (shoulder). 6.40-6.95 11.; NMR has 1.48ppm and 1.52 ppm peaks.

ST AU 6538P .976 ST AU SMITH L BA SL' 6633 l5.6 NE CA 8I93 15.6 HE SP9955 31.3 ES CO 9637 I25 PR VU 6896 SA PA I I737 I25 ST AU CHP 125 ST AU53-l80 I25 B0 BR 46l7 251) EN AE 130411 250 ES lN 65-l 250 KL PN 10031250 What is claimed is: l. A compound of the formula:

F CCHCONHI/ S 3 0 N CH R 2 CO R in which R is H or -OH;

R'- is H or an alkali metal cation; and

R" is H. (lower)alkanoyloxy or N-pyridinium.

2. The compound of claim 1 which is 7-(3,3.3-trifluoro-2-phenylpropionamido)cephalosporanic acid and the alkali metalsalts thereof.

3. The compound of claim 1 which is 3-methyl-8- oxo7-( 3 .3.3-trifluoro-2-phenylpropionamido )-5-thia-1-azabicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid and the alkali metalsalts thereof. 1

1. A compound of the formula:
 1. A COMPOUND OF THE FORMULA:
 2. Thecompound of claim 1 which is7-(3,3,3-trifluoro-2-phenylpropionamido)cephalosporanic acid and thealkali metal salts thereof.